{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T13:06:31Z","timestamp":1790168791904,"version":"4.1.0"},"reference-count":123,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Chronic musculoskeletal disorders, including osteoarthritis, rheumatoid arthritis, and tendinopathies, converge on persistent synovial inflammation, matrix catabolism, and impaired repair. This review synthesizes molecular evidence that the cholinergic anti-inflammatory pathway (CAP), the efferent vagal arm of the inflammatory reflex, behaves as a rheostat of the musculoskeletal microenvironment. Activation of the \u03b17 nicotinic acetylcholine receptor (\u03b17nAChR) on macrophages, chondrocytes, osteoblasts, and synoviocytes suppresses nuclear factor-\u03baB (NF-\u03baB) and NLRP3 inflammasome signaling, downregulates MMP-1, MMP-3, and MMP-13, and reduces osteoblast RANKL production; effects on OPG and on the RANKL\/OPG ratio under vagal stimulation remain uncharacterized, while favoring a pro-resolution M2-like macrophage program; context-dependent pro-inflammatory responses have also been reported. Bidirectional CAP and mesenchymal stromal cell (MSC) crosstalk indicates that MSCs both sense cholinergic cues and require an intact vagal arc for full immunomodulation. Along the gut\u2013vagus\u2013joint axis, dysbiosis and endotoxin translocation attenuate vagal signaling and amplify systemic inflammatory tone. Because orthobiologics such as platelet-rich plasma, bone marrow aspirate concentrate, and MSCs act within this milieu, cholinergic tone appears associated with the terrain that conditions their efficacy. Heart rate variability stratification and vagal neuromodulation may represent testable adjuncts, although prospective validation in orthobiologic populations remains absent. Preclinical and early clinical evidence is critically appraised throughout.<\/jats:p>","DOI":"10.3390\/ijms27198496","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T12:36:07Z","timestamp":1790166967000},"page":"8496","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Vagus Nerve\u2013Macrophage Connection: Tuning the Rheostat of Regenerative Medicine"],"prefix":"10.3390","volume":"27","author":[{"given":"Alexandre Henrique Caetano de","family":"Parma","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil"},{"name":"Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3138-2886","authenticated-orcid":false,"given":"Jo\u00e3o Prot\u00e1sio","family":"Netto","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Traumatology, Federal University of Tocantins (UFT), Palmas 77001-090, TO, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7415-3953","authenticated-orcid":false,"given":"Andr\u00e9","family":"Kruel","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil"},{"name":"Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0725-7940","authenticated-orcid":false,"given":"Luyddy","family":"Pires","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil"},{"name":"Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom\u00e1s","family":"Mosaner","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil"},{"name":"Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1195-227X","authenticated-orcid":false,"given":"Daniel","family":"Jorge","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil"},{"name":"Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3322-0598","authenticated-orcid":false,"given":"Stephany","family":"Huber","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil"},{"name":"Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 F\u00e1bio","family":"Lana","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil"},{"name":"Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/s41392-024-01845-w","article-title":"Pathology of pain and its implications for therapeutic interventions","volume":"9","author":"Cao","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e1362","DOI":"10.1097\/AJP.0000000000001362","article-title":"Pathophysiology of Chronic Pain","volume":"42","author":"Lyndon","year":"2026","journal-title":"Clin. J. Pain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.2147\/JPR.S456202","article-title":"Role of Nutrition in the Management of Patients with Chronic Musculoskeletal Pain","volume":"17","author":"Cuomo","year":"2024","journal-title":"J. Pain Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1080\/14728222.2020.1784142","article-title":"Nutritional intervention in chronic pain: An innovative way of targeting central nervous system sensitization?","volume":"24","author":"Nijs","year":"2020","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.autneu.2013.12.007","article-title":"The cholinergic anti-inflammatory pathway: A critical review","volume":"182","author":"Martelli","year":"2014","journal-title":"Auton. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"100696","DOI":"10.1016\/j.xcrm.2022.100696","article-title":"Manipulation of the inflammatory reflex as a therapeutic strategy","volume":"3","author":"Kelly","year":"2022","journal-title":"Cell Rep. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1111\/j.1365-2796.2010.02321.x","article-title":"The pulse of inflammation: Heart rate variability, the cholinergic anti-inflammatory pathway and implications for therapy","volume":"269","author":"Huston","year":"2010","journal-title":"J. Intern. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"210","DOI":"10.2119\/2006-00108.Goldstein","article-title":"Cholinergic Anti-Inflammatory Pathway Activity and High Mobility Group Box-1 (HMGB1) Serum Levels in Patients with Rheumatoid Arthritis","volume":"13","author":"Goldstein","year":"2007","journal-title":"Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1111\/joim.12626","article-title":"Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis","volume":"282","author":"Koopman","year":"2017","journal-title":"J. Intern. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1007\/s10787-021-00812-z","article-title":"Cholinergic anti-inflammatory pathway and connective tissue diseases","volume":"29","author":"Hajiasgharzadeh","year":"2021","journal-title":"Inflammopharmacology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"191","DOI":"10.5114\/reum\/168503","article-title":"Matrix metalloproteinases in rheumatoid arthritis and osteoarthritis: A state of the art review","volume":"61","author":"Pulik","year":"2023","journal-title":"Reumatologia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1111\/os.13993","article-title":"Emerging Roles of Macrophage Polarization in Osteoarthritis: Mechanisms and Therapeutic Strategies","volume":"16","author":"Yuan","year":"2024","journal-title":"Orthop. Surg."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bonaz, B., Bazin, T., and Pellissier, S. (2018). The Vagus Nerve at the Interface of the Microbiota-Gut-Brain Axis. Front. Neurosci., 12.","DOI":"10.3389\/fnins.2018.00049"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"111702","DOI":"10.1016\/j.brainresbull.2025.111702","article-title":"A vagus-dependent gut microbiota-metabolite axis drives chronic inflammatory pain and working-memory deficits in mice","volume":"234","author":"Yue","year":"2026","journal-title":"Brain Res. Bull."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3002","DOI":"10.1038\/s41380-023-02071-6","article-title":"Gut microbiota changes require vagus nerve integrity to promote depressive-like behaviors in mice","volume":"28","author":"Siopi","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Liu, F.J., Wu, J., Gong, L.J., Yang, H.S., and Chen, H. (2024). Non-invasive vagus nerve stimulation in anti-inflammatory therapy: Mechanistic insights and future perspectives. Front. Neurosci., 18.","DOI":"10.3389\/fnins.2024.1490300"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"114941","DOI":"10.1016\/j.intimp.2025.114941","article-title":"Neuro-immune interactions: Exploring the anti-inflammatory role of the vagus nerve","volume":"159","author":"Liu","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zouali, M. (2023). Pharmacological and Electroceutical Targeting of the Cholinergic Anti-Inflammatory Pathway in Autoimmune Diseases. Pharmaceuticals, 16.","DOI":"10.3390\/ph16081089"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1186\/s13018-024-05052-9","article-title":"Research progress on macrophage polarization during osteoarthritis disease progression: A review","volume":"19","author":"Yin","year":"2024","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"113056","DOI":"10.1016\/j.intimp.2024.113056","article-title":"The role of macrophage polarization in rheumatoid arthritis and osteoarthritis: Pathogenesis and therapeutic strategies","volume":"142","author":"Chang","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wang, L., and He, C. (2022). Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.967193"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.joca.2020.01.007","article-title":"Macrophages regulate the progression of osteoarthritis","volume":"28","author":"Zhang","year":"2020","journal-title":"Osteoarthr. Cartil."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Zhu, X., Dai, S., Xia, B., Gong, J., and Ma, B. (2021). Activation of the alpha 7 nicotinic acetylcholine receptor mitigates osteoarthritis progression by inhibiting NF-\u03baB\/NLRP3 inflammasome activation and enhancing autophagy. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0256507"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.actbio.2021.12.006","article-title":"The immune microenvironment in cartilage injury and repair","volume":"140","author":"Li","year":"2022","journal-title":"Acta Biomater."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zhang, K., Wang, Z., He, J., Lu, L., Wang, W., Yang, A., Xie, H., Huang, L., Huang, Y., and Zhang, K. (2025). Mechanisms of synovial macrophage polarization in osteoarthritis pathogenesis and their therapeutic implications. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1637731"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1136\/annrheumdis-2018-213450","article-title":"Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2","volume":"77","author":"Zhang","year":"2018","journal-title":"Ann. Rheum. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"qiaf077","DOI":"10.1093\/jleuko\/qiaf077","article-title":"TFEB-mediated proinflammatory response in murine macrophages induced by acute Alpha7 nicotinic receptor activation","volume":"117","author":"Honwad","year":"2025","journal-title":"J. Leukoc. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5267","DOI":"10.1038\/s41598-026-35757-2","article-title":"The role of the \u03b17 nicotinic acetylcholine receptor in promoting M2 macrophage polarization at inflammatory sites","volume":"16","author":"Mihara","year":"2026","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zheng, Z., Lin, L., Lin, H., Zhou, J., Wang, Z., Wang, Y., Chen, J., Lai, C., Li, R., and Shen, Z. (2025). Acetylcholine from tuft cells promotes M2 macrophages polarization in Hirschsprung-associated enterocolitis. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1559966"},{"key":"ref_30","first-page":"971","article-title":"Activation of the \u03b17 nicotinic receptor promotes lipopolysaccharide-induced conversion of M1 microglia to M2","volume":"9","author":"Zhang","year":"2017","journal-title":"Am. J. Transl. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"509","DOI":"10.2147\/DDDT.S348836","article-title":"\u03b1-Mangostin Treats Early-Stage Adjuvant-Induced Arthritis of Rat by Regulating the CAP-SIRT1 Pathway in Macrophages","volume":"16","author":"Chen","year":"2022","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.2147\/DDDT.S249865","article-title":"Activation of Cholinergic Anti-Inflammatory Pathway in Peripheral Immune Cells Involved in Therapeutic Actions of \u03b1-Mangostin on Collagen-Induced Arthritis in Rats","volume":"14","author":"Yin","year":"2020","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"157684","DOI":"10.1016\/j.phymed.2025.157684","article-title":"Notopterol attenuates synovitis via \u03b17nAChR-dependent metabolic reprogramming of macrophage polarisation","volume":"150","author":"Chen","year":"2026","journal-title":"Phytomedicine"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"110676","DOI":"10.1016\/j.intimp.2023.110676","article-title":"GTS-21 alleviates murine collagen-induced arthritis through inhibition of peripheral monocyte trafficking into the synovium","volume":"122","author":"Bai","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Levine, Y.A., Koopman, F.A., Faltys, M., Caravaca, A., Bendele, A., Zitnik, R., Vervoordeldonk, M.J., and Tak, P.P. (2014). Neurostimulation of the Cholinergic Anti-Inflammatory Pathway Ameliorates Disease in Rat Collagen-Induced Arthritis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0104530"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1038\/s41467-019-08721-0","article-title":"Noninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis","volume":"10","author":"Zachs","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_37","first-page":"114","article-title":"Stimulation of nicotinic acetylcholine receptors attenuates collagen-induced arthritis in mice","volume":"60","author":"Lebre","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1136\/ard.2009.118554","article-title":"Role of the cholinergic nervous system in rheumatoid arthritis: Aggravation of arthritis in nicotinic acetylcholine receptor \u03b17 subunit gene knockout mice","volume":"69","author":"Stoof","year":"2010","journal-title":"Ann. Rheum. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1186\/s13075-018-1759-9","article-title":"The effect of the cholinergic anti-inflammatory pathway on collagen-induced arthritis involves the modulation of dendritic cell differentiation","volume":"20","author":"Liu","year":"2018","journal-title":"Arthritis Res. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e13092","DOI":"10.1111\/sji.13092","article-title":"The role of the cholinergic anti-inflammatory pathway in autoimmune rheumatic diseases","volume":"94","author":"Lv","year":"2021","journal-title":"Scand. J. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1016\/j.acthis.2019.07.001","article-title":"Expression and localization analyses of the cholinergic anti-inflammatory pathway and \u03b17nAchR in different tissues of rats with rheumatoid arthritis","volume":"121","author":"Li","year":"2019","journal-title":"Acta Histochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1007\/s11655-020-3471-2","article-title":"Chinese Herbal Formula Ermiao Powder (\u4e8c\u5999\u6563) Regulates Cholinergic Anti-inflammatory Pathway in Rats with Rheumatoid Arthritis","volume":"26","author":"Li","year":"2020","journal-title":"Chin. J. Integr. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1007\/s11481-015-9601-5","article-title":"Activation of the Macrophage \u03b17 Nicotinic Acetylcholine Receptor and Control of Inflammation","volume":"10","year":"2015","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"121114","DOI":"10.1016\/j.biomaterials.2021.121114","article-title":"Resolution of inflammation in bone regeneration: From understandings to therapeutic applications","volume":"277","author":"Newman","year":"2021","journal-title":"Biomaterials"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41584-023-00966-w","article-title":"Matrix metalloproteinases in arthritis: Towards precision medicine","volume":"19","author":"Grillet","year":"2023","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.joca.2021.02.005","article-title":"The cholinergic system in joint health and osteoarthritis: A narrative-review","volume":"29","author":"Lauwers","year":"2021","journal-title":"Osteoarthr. Cartil."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1002\/art.24470","article-title":"The \u03b17 nicotinic acetylcholine receptor on fibroblast-like synoviocytes and in synovial tissue from rheumatoid arthritis patients: A possible role for a key neurotransmitter in synovial inflammation","volume":"60","author":"Maanen","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"16157","DOI":"10.2147\/JIR.S545945","article-title":"Nicotine Attenuates Chondrocyte Inflammation via the \u03b17nAChR-Mediated Inhibition of the HMGB1\/TLR4\/NF-\u03baB Signaling Pathway","volume":"18","author":"Lin","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1002\/JLB.3MA0121-024RRRR","article-title":"Sinomenine increases adenosine A2A receptor and inhibits NF-\u03baB to inhibit arthritis in adjuvant-induced-arthritis rats and fibroblast-like synoviocytes through \u03b17nAChR","volume":"110","author":"Yi","year":"2021","journal-title":"J. Leukoc. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Courties, A., Petit, J., Do, A., Legris, M., Kouki, I., Pigenet, A., Sacitharan, P.K., Ehkirch, F.P., Berenbaum, F., and Sellam, J. (2022). Alpha-7 Nicotinic Receptor Dampens Murine Osteoblastic Response to Inflammation and Age-Related Osteoarthritis. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.842538"},{"key":"ref_51","first-page":"237","article-title":"Effects of transcutaneous auricular vagus nerve stimulation on bone and cartilage destruction in rats with rheumatoid arthritis","volume":"47","author":"Yan","year":"2022","journal-title":"Zhen Ci Yan Jiu"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2580","DOI":"10.1016\/j.biocel.2013.08.018","article-title":"The NF-\u03baB signalling pathway in osteoarthritis","volume":"45","author":"Rigoglou","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4361","DOI":"10.1093\/nar\/29.21.4361","article-title":"IL-1 induces collagenase-3 (MMP-13) promoter activity in stably transfected chondrocytic cells: Requirement for Runx-2 and activation by p38 MAPK and JNK pathways","volume":"29","author":"Mengshol","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.bbamcr.2010.01.003","article-title":"The tissue inhibitors of metalloproteinases (TIMPs): An ancient family with structural and functional diversity","volume":"1803","author":"Brew","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"45539","DOI":"10.1074\/jbc.M303737200","article-title":"Aggrecan Protects Cartilage Collagen from Proteolytic Cleavage","volume":"278","author":"Pratta","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3507","DOI":"10.1002\/jcb.23298","article-title":"ADAMTS-4 and ADAMTS-5: Key enzymes in osteoarthritis","volume":"112","author":"Verma","year":"2011","journal-title":"J. Cell. Biochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/nature03417","article-title":"ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro","volume":"434","author":"Stanton","year":"2005","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1038\/nature03369","article-title":"Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis","volume":"434","author":"Glasson","year":"2005","journal-title":"Nature"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature01658","article-title":"Osteoclast differentiation and activation","volume":"423","author":"Boyle","year":"2003","journal-title":"Nature"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Maruyama, M., Rhee, C., Utsunomiya, T., Zhang, N., Ueno, M., Yao, Z., and Goodman, S.B. (2020). Modulation of the Inflammatory Response and Bone Healing. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.00386"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Elsehrawy, G.G., Ibrahim, M.E., A.moneim, N.H., Hefny, M.A., and El Shaarawy, N.K. (2025). Transcutaneous vagus nerve stimulation as a pain modulator in knee osteoarthritis: A randomized controlled clinical trial. BMC Musculoskelet. Disord., 26.","DOI":"10.1186\/s12891-025-08288-6"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"8284","DOI":"10.1073\/pnas.1605635113","article-title":"Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis","volume":"113","author":"Koopman","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Hart, D.A., and Nakamura, N. (2022). Creating an Optimal In Vivo Environment to Enhance Outcomes Using Cell Therapy to Repair\/Regenerate Injured Tissues of the Musculoskeletal System. Biomedicines, 10.","DOI":"10.3390\/biomedicines10071570"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Xu, W., Yang, Y., Li, N., and Hua, J. (2023). Interaction between Mesenchymal Stem Cells and Immune Cells during Bone Injury Repair. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241914484"},{"key":"ref_65","first-page":"2315","article-title":"Regulation of extracellular bioactive cations in bone tissue microenvironment induces favorable osteoimmune conditions to accelerate in situ bone regeneration","volume":"6","author":"Lin","year":"2021","journal-title":"Bioact. Mater."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2303681","DOI":"10.1002\/adhm.202303681","article-title":"Early-Responsive Immunoregulation Therapy Improved Microenvironment for Bone Regeneration via Engineered Extracellular Vesicles","volume":"13","author":"Lu","year":"2023","journal-title":"Adv. Healthc. Mater."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"29438","DOI":"10.1038\/s41598-024-80050-9","article-title":"The roles of regulatory-compliant media and inflammatory\/oxytocin priming selection in enhancing human mesenchymal stem\/stromal cell immunomodulatory properties","volume":"14","author":"Gardashli","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s13287-020-1578-1","article-title":"Influence of inflammatory conditions provided by macrophages on osteogenic ability of mesenchymal stem cells","volume":"11","author":"Bensiamar","year":"2020","journal-title":"Stem Cell Res. Ther."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41581-018-0023-5","article-title":"Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases","volume":"14","author":"Shi","year":"2018","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1089\/scd.2008.0032","article-title":"Functional Nicotinic and Muscarinic Receptors on Mesenchymal Stem Cells","volume":"18","author":"Hoogduijn","year":"2009","journal-title":"Stem Cells Dev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1089\/scd.2022.0201","article-title":"Acetylcholine Receptors in Mesenchymal Stem Cells","volume":"32","author":"Alqahtani","year":"2023","journal-title":"Stem Cells Dev."},{"key":"ref_72","first-page":"203","article-title":"Alpha 7 subunit of nAChR regulates migration of human mesenchymal stem cells","volume":"4","author":"Schraufstatter","year":"2009","journal-title":"J. Stem Cells"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"5348","DOI":"10.1002\/jcp.26350","article-title":"M2 muscarinic receptor activation inhibits cell proliferation and migration of rat adipose-mesenchymal stem cells","volume":"233","author":"Piovesana","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/s41392-022-01124-6","article-title":"Mesenchymal stromal cells alleviate acute respiratory distress syndrome through the cholinergic anti-inflammatory pathway","volume":"7","author":"Zhang","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"R135","DOI":"10.1152\/ajpregu.00098.2018","article-title":"Wharton\u2019s jelly-derived mesenchymal stem cells attenuate sepsis-induced organ injury partially via cholinergic anti-inflammatory pathway activation","volume":"318","author":"Capcha","year":"2020","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Wang, L., Li, Y., Xu, M., Deng, Z., Zhao, Y., Yang, M., Liu, Y., Yuan, R., Sun, Y., and Zhang, H. (2021). Regulation of Inflammatory Cytokine Storms by Mesenchymal Stem Cells. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.726909"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Everts, P., Onishi, K., Jayaram, P., Lana, J.F., and Mautner, K. (2020). Platelet-Rich Plasma: New Performance Understandings and Therapeutic Considerations in 2020. Int. J. Mol. Sci., 21.","DOI":"10.20944\/preprints202010.0069.v1"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.4252\/wjsc.v13.i8.1072","article-title":"Mesenchymal stem cells as a potential therapeutic tool to cure cognitive impairment caused by neuroinflammation","volume":"13","author":"Skok","year":"2021","journal-title":"World J. Stem Cells"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/nri2711","article-title":"The regulation of IL-10 production by immune cells","volume":"10","author":"Saraiva","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.ceb.2019.07.008","article-title":"SOX9 in cartilage development and disease","volume":"61","author":"Lefebvre","year":"2019","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nrneph.2016.48","article-title":"TGF-\u03b2: The master regulator of fibrosis","volume":"12","author":"Meng","year":"2016","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Kim, G.B., Seo, M.S., Park, W.T., and Lee, G.W. (2020). Bone Marrow Aspirate Concentrate: Its Uses in Osteoarthritis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093224"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Lana, J.F., Purita, J., Jeyaraman, M., de Souza, B.F., Rodrigues, B.L., Huber, S.C., Caliari, C., Santos, G.S., da Fonseca, L.F., and Dallo, I. (2024). Innovative Approaches in Knee Osteoarthritis Treatment: A Comprehensive Review of Bone Marrow-Derived Products. Biomedicines, 12.","DOI":"10.3390\/biomedicines12122812"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"155","DOI":"10.4252\/wjsc.v13.i2.155","article-title":"Platelet-rich plasma vs bone marrow aspirate concentrate: An overview of mechanisms of action and orthobiologic synergistic effects","volume":"13","author":"Lana","year":"2021","journal-title":"World J. Stem Cells"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e12709","DOI":"10.1111\/acel.12709","article-title":"Autophagy controls mesenchymal stem cell properties and senescence during bone aging","volume":"17","author":"Ma","year":"2017","journal-title":"Aging Cell"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1146\/annurev-pathol-121808-102144","article-title":"The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression","volume":"5","author":"Desprez","year":"2010","journal-title":"Annu. Rev. Pathol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1101\/gad.17276711","article-title":"Control of the senescence-associated secretory phenotype by NF-\u03baB promotes senescence and enhances chemosensitivity","volume":"25","author":"Chien","year":"2011","journal-title":"Genes Dev."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s41232-023-00279-1","article-title":"Bone regeneration in inflammation with aging and cell-based immunomodulatory therapy","volume":"43","author":"Kushioka","year":"2023","journal-title":"Inflamm. Regen."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1177\/03635465251395284","article-title":"Platelet-Rich Plasma in the Treatment of Musculoskeletal Disease in 2025 and Beyond","volume":"54","author":"Rothrauff","year":"2026","journal-title":"Am. J. Sports Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"11493","DOI":"10.1038\/s41598-021-90174-x","article-title":"In vitro responses to platelet-rich-plasma are associated with variable clinical outcomes in patients with knee osteoarthritis","volume":"11","author":"Zahir","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.bbi.2019.03.009","article-title":"Heart rate variability and inflammation: A meta-analysis of human studies","volume":"80","author":"Williams","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.bbi.2014.12.017","article-title":"Heart rate variability predicts levels of inflammatory markers: Evidence for the vagal anti-inflammatory pathway","volume":"49","author":"Cooper","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"103116","DOI":"10.1016\/j.autneu.2023.103116","article-title":"Heart rate variability as a marker and predictor of inflammation, nosocomial infection, and sepsis\u2014A systematic review","volume":"249","author":"Adam","year":"2023","journal-title":"Auton. Neurosci."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"100273","DOI":"10.1016\/j.bbih.2021.100273","article-title":"Heart rate variability and circulating inflammatory markers in midlife","volume":"15","author":"Alen","year":"2021","journal-title":"Brain Behav. Immun. Health"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1016\/j.psyneuen.2008.08.007","article-title":"The relationship between heart rate variability and inflammatory markers in cardiovascular diseases","volume":"33","author":"Haensel","year":"2008","journal-title":"Psychoneuroendocrinology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1111\/joim.12295","article-title":"Lower heart rate variability predicts increased level of C-reactive protein 4 years later in healthy, nonsmoking adults","volume":"276","author":"Jarczok","year":"2014","journal-title":"J. Intern. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"80","DOI":"10.3892\/br.2023.1662","article-title":"Linear and non-linear indices of vagal nerve in relation to sex and inflammation in patients with Covid-19","volume":"19","author":"Hunakova","year":"2023","journal-title":"Biomed. Rep."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Mikolaskova, I., Zvarik, M., Szaboova, K., Tibenska, E., Durmanova, V., Suchankova, M., Kollarik, B., Hesko, P., Palacka, P., and Bucova, M. (2024). Association of Sympathovagal Imbalance with Increased Inflammation and Impaired Adaptive Immunity in Bladder Cancer Patients. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252312765"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1167\/iovs.66.13.16","article-title":"Impaired Vagal Tone Function-Based Regulation of Systemic Inflammation in Patients with Neovascular Age-Related Macular Degeneration","volume":"66","author":"Molbech","year":"2025","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"100467","DOI":"10.1016\/j.ocarto.2024.100467","article-title":"Vagotomy accelerates the onset of symptoms during early disease progression and worsens joint-level pathogenesis in a male rat model of chronic knee osteoarthritis","volume":"6","author":"Cruz","year":"2024","journal-title":"Osteoarthr. Cartil. Open"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"ldae016","DOI":"10.1093\/bmb\/ldae016","article-title":"Management of knee osteoarthritis using bone marrow aspirate concentrate: A systematic review","volume":"153","author":"Migliorini","year":"2024","journal-title":"Br. Med. Bull."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Park, D., Koh, H.S., Choi, Y.H., and Park, I. (2025). Bone Marrow Aspirate Concentrate (BMAC) for Knee Osteoarthritis: A Narrative Review of Clinical Efficacy and Future Directions. Medicina, 61.","DOI":"10.20944\/preprints202503.0139.v1"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"393","DOI":"10.3892\/etm.2024.12682","article-title":"Preoperative vagal activity predicts clinical outcomes after total knee replacement","volume":"28","author":"Gitler","year":"2024","journal-title":"Exp. Ther. Med."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Liu, J., Liu, S., Gao, L., Li, G., Xu, J., Sun, Y., Wang, J., and Shi, B. (2021). Predicting Post-operative Blood Inflammatory Biomarkers Using Pre-operative Heart Rate Variability in Patients with Cervical Cancer. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.696208"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Hildenborg, M., K\u00e5hlin, J., Granath, F., Schening, A., Granstr\u00f6m, A., Ebberyd, A., Klevenvall, L., Zetterberg, H., Han, J., and Schlegel, T.T. (2022). The Neuroimmune Response to Surgery\u2014An Exploratory Study of Trauma-Induced Changes in Innate Immunity and Heart Rate Variability. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.911744"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11926-022-01094-2","article-title":"Neuromodulation as a Potential Disease-Modifying Therapy for Osteoarthritis","volume":"25","author":"Cruz","year":"2022","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1177\/1947603517741169","article-title":"Bone Marrow Aspirate Concentrate for Cartilage Defects of the Knee: From Bench to Bedside Evidence","volume":"9","author":"Cotter","year":"2017","journal-title":"Cartilage"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2325967115625481","DOI":"10.1177\/2325967115625481","article-title":"Concentrated Bone Marrow Aspirate for the Treatment of Chondral Injuries and Osteoarthritis of the Knee","volume":"4","author":"Chahla","year":"2016","journal-title":"Orthop. J. Sports Med."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12974-023-03001-7","article-title":"Cholinergic signaling via the \u03b17 nicotinic acetylcholine receptor regulates the migration of monocyte-derived macrophages during acute inflammation","volume":"21","author":"Keever","year":"2024","journal-title":"J. Neuroinflammation"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"3122","DOI":"10.1038\/s41467-023-38505-6","article-title":"Vagus nerve stimulation primes platelets and reduces bleeding in hemophilia A male mice","volume":"14","author":"Fritz","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1161\/ATVBAHA.110.218297","article-title":"Human Platelets Express Functional \u03b17-Nicotinic Acetylcholine Receptors","volume":"31","author":"Schedel","year":"2011","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3109\/09537104.2015.1026803","article-title":"Megakaryocytes and platelets express nicotinic acetylcholine receptors but nicotine does not affect megakaryopoiesis or platelet function","volume":"27","author":"Schedel","year":"2015","journal-title":"Platelets"},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Jankauskait\u0117, L., Malinauskas, M., and Snipaitiene, A. (2022). Effect of stimulated platelets in COVID-19 thrombosis: Role of \u03b17 nicotinic acetylcholine receptor. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.1037369"},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Wu, X., Liu, Y., Zou, C., He, F., Guo, F., Liu, S., Fan, Y., Zhu, X., Zhou, Q., and Shu, D. (2025). Nicotine\u2019s impact on platelet function: Insights into hemostasis mechanisms. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1512142"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1177\/03635465211072554","article-title":"Bone Marrow Aspirate Concentrate Is Equivalent to Platelet-Rich Plasma for the Treatment of Knee Osteoarthritis at 2 Years: A Prospective Randomized Trial","volume":"50","author":"Anz","year":"2022","journal-title":"Am. J. Sports Med."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1016\/j.arthro.2023.03.001","article-title":"Patients with Knee Osteoarthritis Who Receive Platelet-Rich Plasma or Bone Marrow Aspirate Concentrate Injections Have Better Outcomes Than Patients Who Receive Hyaluronic Acid: Systematic Review and Meta-analysis","volume":"39","author":"Belk","year":"2023","journal-title":"Arthroscopy"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.1016\/j.arthro.2021.02.045","article-title":"Intra-Articular Injections of Platelet-Rich Plasma, Adipose Mesenchymal Stem Cells, and Bone Marrow Mesenchymal Stem Cells Associated with Better Outcomes Than Hyaluronic Acid and Saline in Knee Osteoarthritis: A Systematic Review and Network Meta-analysis","volume":"37","author":"Zhao","year":"2021","journal-title":"Arthroscopy"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"117954412093108","DOI":"10.1177\/1179544120931086","article-title":"Patient-Reported Outcomes After Platelet-Rich Plasma, Bone Marrow Aspirate, and Adipose-Derived Mesenchymal Stem Cell Injections for Symptomatic Knee Osteoarthritis","volume":"13","author":"Estrada","year":"2020","journal-title":"Clin. Med. Insights Arthritis Musculoskelet. Disord."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Liao, C.D., Chen, H.C., Huang, M.H., Liou, T.H., Lin, C.L., and Huang, S.W. (2023). Comparative Efficacy of Intra-Articular Injection, Physical Therapy, and Combined Treatments on Pain, Function, and Sarcopenia Indices in Knee Osteoarthritis: A Network Meta-Analysis of Randomized Controlled Trials. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076078"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"ziag078","DOI":"10.1093\/jbmrpl\/ziag078","article-title":"Transcutaneous vagal nerve stimulation improves post-traumatic osteoarthritis pain in mice","volume":"10","author":"Yadav","year":"2026","journal-title":"JBMR Plus"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.biopsych.2005.05.024","article-title":"Effects of 12 Months of Vagus Nerve Stimulation in Treatment-Resistant Depression: A Naturalistic Study","volume":"58","author":"Rush","year":"2005","journal-title":"Biol. Psychiatry"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"e13911","DOI":"10.1111\/nmo.13911","article-title":"A 12-month pilot study outcomes of vagus nerve stimulation in Crohn\u2019s disease","volume":"32","author":"Sinniger","year":"2020","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"e01202","DOI":"10.7554\/eLife.01202","article-title":"Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis","volume":"2","author":"Scher","year":"2013","journal-title":"eLife"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8496\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T12:38:29Z","timestamp":1790167109000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8496"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,23]]},"references-count":123,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198496"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198496","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,23]]}}}